Scleroderma is a rare, long-term autoimmune disease in which normal tissue is replaced with dense, thick fibrous tissue. Normally, the immune system helps defend the body against disease and infection. In people with scleroderma, the immune system triggers fibroblast cells to produce too much of the protein collagen. The extra collagen becomes deposited in the skin and organs, causing hardening and thickening that is similar to the scarring process. Although scleroderma most often affects the skin, it also can affect other parts of the body, including the lungs, and in its most severe forms scleroderma can be life-threatening. Scleroderma-related interstitial lung disease is one example of a life-threatening scleroderma condition. In people with symptomatic scleroderma-related interstitial lung disease, scarring occurs in the delicate lung tissue, compromising lung function. The purpose of this study is to determine whether people with symptomatic scleroderma-related interstitial lung disease experience more respiratory benefits from treatment with a 2-year course of mycophenolate mofetil or treatment with a 1-year course of oral cyclophosphamide.

24 months of oral mycophenolate mofetil, up to a maximal dose of 1.5 grams twice daily as tolerated

Other Name: CellCept

Experimental: Cyclophosphamide Arm

Participants will receive oral cyclophosphamide for 1 year, followed by placebo for 1 year.

Drug: Cyclophosphamide

12 months of oral cyclophosphamide, up to a maximal dose of 2 mg/kg daily as tolerated

Other Name: Cytoxan

Drug: Placebo

12 months of placebo will be delivered to participants in the Cyclophosphamide arm during the second year in order to maintain the blind with the Mycophenolate arm, which receives drug for the entire 2 years.

Other Name: Sugar Pill

Detailed Description:

Interstitial lung disease describes a condition in which the lung tissue has become scarred or inflamed. Interstitial lung disease caused by scleroderma, specifically seen as progressive pulmonary fibrosis, occurs in approximately 40 percent of patients with scleroderma and has emerged as the leading overall cause of death.

In a previous study, the Scleroderma Lung Study I (SLS I), investigators evaluated a 1-year cyclophosphamide (CYC) treatment for people with scleroderma-related interstitial lung disease. The study results demonstrated statistically significant improvements in forced vital capacity, total lung capacity, dyspnea, Rodnan skin scores, and several measures of quality of life. However, when patients were followed for another year after completing their CYC therapy, the beneficial effects of CYC waned and were no longer significant by the 24-month follow-up. Preliminary information suggests that an alternative immunosuppressive medication, mycophenolate mofetil (MMF), may be effective in treating this disease, be given for longer periods, and result in fewer side effects.

This study, the Scleroderma Lung Study II (SLS II), will compare the safety and efficacy of a 2-year treatment with MMF versus a 1-year treatment with CYC. Specifically, investigators will determine whether MMF produces similar or better improvements in lung capacity and fewer side effects throughout the entire 2-year period.

Participation will include about 21 study visits over a 2-year period. Eligible participants will be randomly assigned to receive either MMF twice daily for 2 years or CYC once daily for 1 year, followed by placebo for 1 year. Blood and urine samples will be collected every 2 weeks for the first 2 months and then once a month for the remainder of the study. Every 3 months, participants will attend study visits that will include pulmonary function tests, blood and urine sampling, a physical exam, and questionnaires about current health and medications. At the final study visit, participants will also undergo a high resolution computerized tomography (HRCT) scan and possibly a punch biopsy.

Eligibility

Ages Eligible for Study:

18 Years and older

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

The presence of either limited (cutaneous thickening distal but not proximal to elbows and knees, with or without facial involvement) or diffuse (cutaneous thickening proximal to elbows and knees, often involving the chest or abdomen) scleroderma, as determined by American College of Rheumatology criteria

Dyspnea on exertion (grade 2 on the Magnitude of Task component of the Mahler Modified Dyspnea Index)

FVC less than or equal to 80 percent of predicted value at screening and less than or equal to 85 percent predicted at baseline

Onset of the first non-Raynaud manifestation of SSc within the prior 84 months

Presence of any ground glass opacification on thoracic high resolution computerized tomography (HRCT)

Repeat FVC at the baseline visit (Visit 2) within 10 percent of the FVC measured at screening and less than or equal to 85 percent predicted.

Exclusion Criteria:

FVC less than 45 percent of predicted value at either screening or baseline

Carbon monoxide diffusing capacity (DLCO) (HBg-corrected) less than 30 percent of predicted value and less than 40 percent of predicted when documentation of pulmonary artery pressures by echocardiogram, right heart catheterization or magnetic resonance imaging identifies clinically significant pulmonary hypertension. All participants with a DLCO less than 40 percent predicted must have documentation of pulmonary artery pressures in order to be considered for inclusion.

FEV1/FVC ratio less than 65 percent at either screening or baseline

Clinically significant abnormalities on HRCT not attributable to scleroderma

Diagnosis of clinically significant resting pulmonary hypertension requiring treatment, as ascertained before study evaluation or as part of a standard of care clinical assessment performed outside of the study protocol

Current use, or use within the 30 days prior to random assignment, of prednisone (or equivalent) in doses of more than 10 mg/day

If of child bearing potential (a female participant <55 years of age who has not been postmenopausal for > 5 years and who has not had a hysterectomy and/or oophorectomy), failure to employ two reliable means of contraception (which may include surgical sterilization, barrier methods, spermicidals, intrauterine devices, and/or hormonal contraception).

Use of contraindicated medications; more information on this criterion can be found in the study protocol

Smoking of cigars, pipes, or cigarettes in the 6 months before study entry

Use of medications with putative disease-modifying properties within the past month (e.g., D-penicillamine, azathioprine, methotrexate, Potaba)

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00883129

Locations

United States, California

David Geffen School of Medicine at UCLA

Los Angeles, California, United States, 90095

University of California, San Francisco

San Francisco, California, United States, 94143

United States, Colorado

National Jewish Health

Denver, Colorado, United States, 80206

United States, District of Columbia

Georgetown University School of Medicine

Washington, District of Columbia, United States, 20057

United States, Illinois

Feinberg School of Medicine, Northwestern University

Chicago, Illinois, United States, 60611

University of Illinois at Chicago, College of Medicine

Chicago, Illinois, United States, 60612

United States, Maryland

Johns Hopkins University School of Medicine

Baltimore, Maryland, United States, 21205

United States, Massachusetts

Boston University School of Medicine

Boston, Massachusetts, United States, 02118

United States, Michigan

University of Michigan Medical School

Ann Arbor, Michigan, United States, 48109

United States, Minnesota

University of Minnesota

Minneapolis, Minnesota, United States, 55454

United States, New Jersey

University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School